RESUMEN
BACKGROUND: Uncorrected obesity facilitates premature aging and cardiovascular anomalies. This study examined the interaction between obesity and aging on cardiac remodeling and contractile function. METHODS: Cardiac echocardiographic geometry, function, morphology, intracellular Ca2+ handling, oxidative stress (DHE fluorescence), STAT3 and stress signaling were evaluated in young (3-mo) and old (12- and 18-mo) lean and leptin deficient ob/ob obese mice. Cardiomyocytes from young and old lean and ob/ob mice were treated with leptin (1 nM) for 4 h in vitro prior to assessment of mechanical and biochemical properties. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obese mice at young and old age were evaluated for comparison. RESULTS: Our results displayed reduced survival in ob/ob mice. Obesity but less likely older age dampened echocardiographic, geometric, cardiomyocyte function and intracellular Ca2+ properties, elevated O2- and p47phox NADPH oxidase levels with a more pronounced geometric change at older age. Immunoblot analysis revealed elevated p47phox NADPH oxidase and dampened phosphorylation of STAT3, with a more pronounced response in old ob/ob mice, the effects were restored by leptin. Obesity and aging inhibited phosphorylation of Akt, eNOS, AMPK, and p38 while promoting phosphorylation of JNK and IκB. Leptin reconciled cardiomyocyte dysfunction, O2- yield, p47phox upregulation, STAT3 dephosphorylation and stress signaling in ob/ob mice although its action on stress signaling cascades were lost at old age. High fat diet-induced and db/db obesity displayed aging-associated cardiomyocyte anomalies reminiscent of ob/ob model albeit lost leptin response. CONCLUSIONS: Our data suggest disparate age-associated obesity response in cardiac remodeling and contractile dysfunction due to phosphorylation of Akt, eNOS and stress signaling-related oxidative stress.
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Envejecimiento , Leptina , Miocardio , Obesidad , Animales , Ratones , Leptina/fisiología , Ratones Obesos , NADPH Oxidasas , Proteínas Proto-Oncogénicas c-akt , Remodelación Ventricular , Miocardio/patología , Estrés Oxidativo , Estrés FisiológicoRESUMEN
BACKGROUND: Patients with gastric cancer often suffer from generalized and progressive reduction of skeletal muscle mass and strength, which negatively affects the quality of life (QOL). In this study, we explored the impact of sarcopenia on QOL and overall survival (OS). METHODS: From December 2015 to June 2017, 135 patients underwent radical gastrectomy at the First Affiliated Hospital of Wenzhou Medical University. Based on the diagnostic criteria of the Asian Working Group for Sarcopenia (AWGS), data including handgrip strength, 6-m gait speed and muscle mass were collected and analyzed. EORTC QLQ-C30 and EORTC QLQ-STO22 were used to evaluate the QOL before surgery, 1, 3 and 6 months after surgery. RESULTS: A total of 27 out of the 135 patients (20.00%) were diagnosed with sarcopenia. Compared with non-sarcopenia group, patients in sarcopenia group had a higher incidence of postoperative complications (14.80% vs. 40.70%, p = 0.003), and more hospitalization costs (p = 0.029). The scores of eating restriction (p = 0.026), anxiety (p = 0.045) and body image (p = 0.046) were significantly higher in sarcopenia group at postoperative 6 months. Besides, sarcopenia was an independent risk factor for global health status at 6 months after operation (OR: 2.881, 95% CI: 1.110-7.475, p = 0.030) and OS (HR: 3.140, 95% CI: 1.255-7.855, p = 0.014). Other factors, including tumor stage III and the postoperative complications, had negative influences on OS. CONCLUSION: Sarcopenia is a predictive factor of poor QOL and prognosis in patients with gastric cancer.
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Adenocarcinoma/cirugía , Gastrectomía , Complicaciones Posoperatorias/epidemiología , Calidad de Vida , Sarcopenia/epidemiología , Neoplasias Gástricas/cirugía , Adenocarcinoma/epidemiología , Adenocarcinoma/patología , Anciano , Anciano de 80 o más Años , Ansiedad/epidemiología , Femenino , Costos de la Atención en Salud/estadística & datos numéricos , Humanos , Masculino , Persona de Mediana Edad , Estadificación de Neoplasias , Pronóstico , Neoplasias Gástricas/epidemiología , Neoplasias Gástricas/patología , Tasa de SupervivenciaRESUMEN
OBJECTIVE: Inflammation and oxidative stress play a key role in the initiation, propagation, and development of atherosclerosis. Arterial baroreflex (ABR) dysfunction induced by sinoaortic denervation (SAD) promoted the development of atherosclerosis in ApoE-/- mice. The present work was designed to examine whether ABR deficiency affected inflammation and oxidative stress via α7 nicotinic acetylcholine receptor (α7nAChR) leading to the aggravation of atherosclerosis in mice. METHODS AND RESULTS: ApoE-/- mice were fed with a high-cholesterol diet for 6weeks and half of the mice received sinoaortic denervation that destroyed ABR. We studied the expression of vesicular acetylcholine transporter (VAChT), α7nAChR and levels of inflammatory response and oxidative stress. The results showed that baroreflex dysfunction could promote atherosclerosis, meanwhile, decrease the expression of VAChT and α7nAChR and significantly increase the levels of oxidative stress and inflammation in SAD mice. After treated with PNU-282987 (a selective α7nAChR agonist, 0.53mg/kg/day) for 6weeks in SAD and Sham mice, we found that PNU-282987 could attenuate atherosclerosis and significantly decreased oxidative stress and inflammation after SAD. In addition, α7nAChR+/+ and α7nAChR-/- mice fed with a high-cholesterol diet for 8weeks were co-treated with ketanserin (0.6mg/kg/day), a drug that can enhance baroreflex sensitivity (BRS). Ketanserin could alleviate atherosclerosis and markedly decrease oxidative stress and inflammation in α7nAChR+/+ mice. But there were no effects in α7nAChR knockout mice. CONCLUSIONS: Our results demonstrate that ABR dysfunction aggravates atherosclerosis in mice via the vagus-ACh-α7nAChR-inflammation and oxidative stress pathway.
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Aterosclerosis/patología , Barorreflejo/fisiología , Inflamación/patología , Receptor Nicotínico de Acetilcolina alfa 7/metabolismo , Animales , Apolipoproteínas E/genética , Arterias/fisiología , Benzamidas/farmacología , Compuestos Bicíclicos con Puentes/farmacología , Modelos Animales de Enfermedad , Ketanserina/farmacología , Ratones , Ratones Noqueados , Estrés Oxidativo/fisiología , Receptor Nicotínico de Acetilcolina alfa 7/genéticaRESUMEN
To investigate the applicability of astragaloside IV (AG) for the treatment of refractory neuropathic pain, we systemically evaluated the antinociceptive activity of AG in the animal model of chronic constriction injury. We studied behaviors, electrophysiology, and biochemistry from day 2 to day 23 after the surgery. We found that when administered intraperitoneally at the dose of 60 mg/kg, AG caused significant inhibition of allodynia and hyperalgesia induced by mechanic and thermal stimuli as well as downregulation of the expressions of a series of proteins involved in mediating neuropathic pain in the dorsal root ganglia, such as P2X purinoceptor 3, glial cell-derived neurotrophic factor, glial cell-derived neurotrophic factor family receptor α1, and transient receptor potential cation channel subtypes A1 and V1. Further investigation showed that AG restored the nerve conduction velocity and the histological structure of the damaged sciatic nerve on day 23 after the surgery. Moreover, results from immunoelectron microscope showed that glial cell-derived neurotrophic factor family receptor α1 induced by AG could form a circular band in the myelin debris between the injured axons and Schwann cells, contributing toward restoration of the damaged nerve. In conclusion, in our animal model, AG effectively inhibited the neuropathic pain induced by chronic constriction injury.
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Analgésicos/farmacología , Dolor Crónico/tratamiento farmacológico , Constricción Patológica/tratamiento farmacológico , Neuralgia/tratamiento farmacológico , Saponinas/farmacología , Nervio Ciático/lesiones , Triterpenos/farmacología , Animales , Peso Corporal/efectos de los fármacos , Peso Corporal/fisiología , Dolor Crónico/etiología , Dolor Crónico/patología , Dolor Crónico/fisiopatología , Constricción Patológica/complicaciones , Constricción Patológica/patología , Constricción Patológica/fisiopatología , Modelos Animales de Enfermedad , Ganglios Espinales/efectos de los fármacos , Ganglios Espinales/fisiopatología , Ganglios Espinales/ultraestructura , Calor , Hiperalgesia/tratamiento farmacológico , Hiperalgesia/patología , Hiperalgesia/fisiopatología , Masculino , Actividad Motora/efectos de los fármacos , Actividad Motora/fisiología , Necrosis/tratamiento farmacológico , Necrosis/etiología , Necrosis/patología , Necrosis/fisiopatología , Conducción Nerviosa/efectos de los fármacos , Conducción Nerviosa/fisiología , Neuralgia/etiología , Neuralgia/patología , Neuralgia/fisiopatología , Ratas Sprague-Dawley , Nervio Ciático/efectos de los fármacos , Nervio Ciático/fisiopatología , Nervio Ciático/ultraestructura , TactoAsunto(s)
Glucósidos/farmacología , Glucósidos/uso terapéutico , Compuestos Heterocíclicos con 2 Anillos/farmacología , Compuestos Heterocíclicos con 2 Anillos/uso terapéutico , Hiperalgesia/tratamiento farmacológico , Umbral del Dolor/efectos de los fármacos , Dolor/tratamiento farmacológico , Analgésicos/química , Analgésicos/farmacología , Analgésicos/uso terapéutico , Análisis de Varianza , Animales , Modelos Animales de Enfermedad , Relación Dosis-Respuesta a Droga , Formaldehído , Glucósidos/química , Compuestos Heterocíclicos con 2 Anillos/química , Ratones , Ratones Endogámicos ICR , Morfina/uso terapéutico , Dolor/inducido químicamente , Dimensión del Dolor , Factores de TiempoRESUMEN
AIM: Baroreflex dysfunction is associated with a higher rate of sudden death after myocardial infarction (MI). Ketanserin enhances baroreflex function in rats. The present work was designed to examine whether ketanserin improves the post-MI cardiac function and to explore the possible mechanism involved. METHODS: Spontaneously hypertensive rats (SHR) were treated with ketanserin (0.3 mg·kg(-1)·d(-1)). Two weeks later, blood pressure and baroreflex function were measured, followed by a ligation of the left coronary artery. The expressions of vesicular acetylcholine transporter (VAChT) and α7 nicotinic acetylcholine receptor (α7-nAChR) in ischemic myocardium, angiogenesis, cardiac function, and left ventricular (LV) remodeling were evaluated subsequently. RESULTS: Ketanserin significantly improved baroreflex sensitivity (0.62±0.21 vs 0.34±0.12 ms/mmHg, P<0.01) and vagal tonic activity (heart rate changes in response to atropine, 54.8±16.2 vs 37.6±13.4 bpm, P<0.01) without affecting the blood pressure or basic heart rate in SHR. Treatment of SHR with ketanserin prominently improved cardiac function and alleviated LV remodeling, as reflected by increases in the ejection fraction, fractional shortening, and LV systolic pressure as well as decreases in LV internal diameter and LV relative weight. The capillary density, vascular endothelial growth factor expression, and blood flow in the ischemic myocardium were significantly higher in the ketanserin-treated group. In addition, ketanserin markedly increased the expression of VAChT and α7-nAChR in ischemic myocardium. CONCLUSION: Ketanserin improved post-MI cardiac function and angiogenesis in ischemic myocardium. The findings provide a mechanistic basis for restoring baroreflex function using ketanserin in the treatment of MI.
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Barorreflejo/efectos de los fármacos , Corazón/efectos de los fármacos , Ketanserina/farmacología , Infarto del Miocardio/fisiopatología , Acetilcolina/metabolismo , Animales , Barorreflejo/fisiología , Ensayo de Inmunoadsorción Enzimática , Corazón/fisiopatología , Infarto del Miocardio/metabolismo , Ratas , Ratas Endogámicas SHR , Factor A de Crecimiento Endotelial Vascular/metabolismoRESUMEN
Nitric oxide (NO) plays an important role in the pathogenesis of endotoxic shock. This work tested the hypothesis that ketanserin could attenuate endotoxic shock by inhibiting the expression of inducible NO synthase (iNOS). The results demonstrated that ketanserin could inhibit iNOS expression in the heart, lungs, liver, and kidneys and nitrate production in the serum upon endotoxic shock in mice. In RAW264.7 cells, ketanserin significantly inhibited the expression of iNOS and decreased the production of NO, TNFα, IL-6, and reactive oxygen species upon lipopolysaccharide (LPS) challenge. Ketanserin also increased the level of ATP and mitochondrial membrane potential in RAW264.7 cells upon LPS exposure. LPS-induced iNOS expression was inhibited by the 5-HT2A receptor antagonist ritanserin and not the α1 receptor antagonist prazosin. Knockdown of 5-HT2A receptor by siRNA abolished the inhibitory effect of ketanserin on the expression of iNOS. These results indicated that the inhibitory effect of ketanserin on the expression of iNOS is mediated by blocking the 5-HT2A receptor. Furthermore, ketanserin significantly inhibited the activation of ERK1/2 and NF-κB signal. Pretreatment with PD184352, a specific inhibitor of ERK1/2, blocked the inhibitory effect of ketanserin on the expression of iNOS and NO production, indicating a critical role for the MEK/ERK1/2 signaling pathway. Collectively, our findings indicate that inhibition of the expression of iNOS via the MEK/ERK pathway mediates the protective effects of ketanserin against LPS-induced shock in mice.
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Antihipertensivos/farmacología , Ketanserina/farmacología , Sistema de Señalización de MAP Quinasas/efectos de los fármacos , Óxido Nítrico Sintasa de Tipo II/biosíntesis , Choque Séptico/metabolismo , Animales , Western Blotting , Modelos Animales de Enfermedad , Ensayo de Cambio de Movilidad Electroforética , Ensayo de Inmunoadsorción Enzimática , Inmunohistoquímica , Lipopolisacáridos/toxicidad , Masculino , Ratones , ARN Interferente Pequeño , TransfecciónAsunto(s)
Infarto Encefálico/etiología , Infarto Encefálico/genética , Infarto de la Arteria Cerebral Media/complicaciones , ATPasas de Translocación de Protón/genética , Animales , Apoptosis/genética , Caspasa 3/metabolismo , Modelos Animales de Enfermedad , Regulación de la Expresión Génica/genética , Humanos , Ratones , Ratones Noqueados , Proteínas Asociadas a Microtúbulos/metabolismoAsunto(s)
Anestesia por Inhalación/métodos , Sistemas de Liberación de Medicamentos/métodos , Éteres Metílicos/metabolismo , Alveolos Pulmonares/metabolismo , Sufentanilo/metabolismo , Adulto , Interacciones Farmacológicas/fisiología , Femenino , Humanos , Masculino , Éteres Metílicos/administración & dosificación , Persona de Mediana Edad , Alveolos Pulmonares/efectos de los fármacos , Sevoflurano , Sufentanilo/administración & dosificación , Volumen de Ventilación Pulmonar/efectos de los fármacos , Volumen de Ventilación Pulmonar/fisiología , Resultado del Tratamiento , Adulto JovenAsunto(s)
Arterias Cerebrales/patología , Accidente Cerebrovascular/patología , Anatomía Transversal , Animales , Conducta Animal , Presión Sanguínea/fisiología , Encéfalo/patología , Femenino , Masculino , Ratas , Ratas Endogámicas SHR , Especificidad de la Especie , Accidente Cerebrovascular/genéticaAsunto(s)
Aneurisma Intracraneal/complicaciones , Aneurisma Intracraneal/patología , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/patología , Animales , Araquidonato 5-Lipooxigenasa/metabolismo , Presión Sanguínea/fisiología , Femenino , Aneurisma Intracraneal/genética , Leucotrienos/biosíntesis , Leucotrienos/genética , Masculino , Adhesión en Parafina , Ratas , Ratas Endogámicas SHR , Accidente Cerebrovascular/genética , Análisis de SupervivenciaRESUMEN
BACKGROUND: Ketanserin, a 5-hydroxytryptamine receptor antagonist, is clinically used as an antihypertensive agent and could enhance baroreflex function. The present work tested the hypothesis that restoration of baroreflex function is an effective treatment for lipopolysaccharide (LPS)-induced shock. METHODS: Kunming mice were injected with LPS (30 mg/kg; intraperitoneal) to induce endotoxic shock. Ketanserin (0.3, 1, 3, or 10 mg/kg; intraperitoneal) was administered immediately after LPS injection. Survival time was monitored, and serum cytokines were analyzed after the onset of LPS. Effects of ketanserin were also examined in IL-10-deficient mice and mice with sinoaortic denervation. Finally, effects of ketanserin on blood pressure, heart rate, and baroreflex sensitivity were examined in Wistar-Kyoto (WKY) rats with endotoxic shock. RESULTS: Ketanserin significantly increased survival time and decreased serum levels of tumor necrosis factor α and interleukin (IL) 1ß in mice with endotoxic shock. At a dose of 10 mg/kg, ketanserin also significantly increased serum IL-10 concentration. The antishock effect of ketanserin was also apparent in IL-10-knockout mice. In mice with sinoaortic denervation, however, ketanserin had little antishock effects. In WKY rats, ketanserin significantly prevented the baroreflex impairment induced by LPS and prolonged the survival time. CONCLUSIONS: Ketanserin could ameliorate endotoxic shock by restoring baroreflex function.
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Barorreflejo/efectos de los fármacos , Ketanserina/farmacología , Ketanserina/uso terapéutico , Antagonistas de la Serotonina/farmacología , Antagonistas de la Serotonina/uso terapéutico , Choque Séptico/tratamiento farmacológico , Animales , Presión Sanguínea/efectos de los fármacos , Relación Dosis-Respuesta a Droga , Frecuencia Cardíaca/efectos de los fármacos , Interleucina-10/sangre , Interleucina-1beta/sangre , Lipopolisacáridos , Masculino , Ratones , Ratas , Ratas Endogámicas WKY , Choque Séptico/sangre , Choque Séptico/inducido químicamente , Análisis de Supervivencia , Factor de Necrosis Tumoral alfa/sangreRESUMEN
Stroke is a major cause of disability and death worldwide. Prevention aimed at risk factors of stroke is the most effective strategy to curb the stroke pandemic. Hypertension is one of the most important risk factors for stroke. Despite the substantial evidence of the benefits of lowering blood pressure, conventional treatment does not normalize the burden of major cardiovascular events in patients with hypertension. Fully understanding the factors involved in the hypertension-induced stroke helps to develop new strategies for stroke prevention. Antihypertensive therapies selected should have positive blood pressure-independent effects on stroke risk. This review summarizes the factors involved in the hypertension-induced stroke, such as oxidative stress, inflammation, and arterial baroreflex dysfunction, and potential strategies for its prevention, therefore, provides clues for clinicians.
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Antihipertensivos/uso terapéutico , Hipertensión/complicaciones , Hipertensión/terapia , Accidente Cerebrovascular/etiología , Accidente Cerebrovascular/prevención & control , Animales , Antihipertensivos/farmacología , Presión Sanguínea/efectos de los fármacos , Presión Sanguínea/fisiología , Humanos , Hipertensión/metabolismo , Fármacos Neuroprotectores/farmacología , Fármacos Neuroprotectores/uso terapéutico , Estrés Oxidativo/efectos de los fármacos , Estrés Oxidativo/fisiología , Factores de Riesgo , Accidente Cerebrovascular/metabolismoRESUMEN
The present study was designed to test the hypothesis that a small dose of ketanserin, which enhances baroreflex activity, prevents the early lesions of atherosclerosis. In experiment 1, baroreflex sensitivity (BRS) was measured in 31 spontaneously hypertensive rats (SHRs) in a conscious state using a computerized blood pressure monitoring system. Four weeks later, the rats were administered vitamin D3 and fed a high-cholesterol diet for 8 weeks to induce atherosclerosis. Then their hearts and aortae were removed for pathological examination. A negative correlation was found between BRS and the scores of coronary (r = -0.460, P < 0.01) and aortic atherosclerosis (r = -0.448, P < 0.05) in SHR. In experiment 2, SHRs were divided into 3 groups (n = 10 in each group) and received a dose of ketanserin of 0.3, 1.0, and 3.0 mg/kg (i.g.), respectively. At the smallest dose (0.3 mg/kg), ketanserin did not lower blood pressure but enhanced BRS. In experiment 3, SHRs were administered vitamin D3, fed a high-cholesterol diet, and simultaneously treated with low-dose ketanserin. The atherosclerosis scores of the treatment group were significantly lower than those of the control group (coronary score: 0.90 ± 0.14 vs. 1.76 ± 0.27, P < 0.05; aortic scores: 1.00 ± 0.39 vs. 2.18 ± 0.41, P < 0.05). In experiment 4, male New Zealand White rabbits were fed a high-cholesterol diet and treated with low-dose ketanserin at the same time. The atherosclerosis scores of the treatment group were significantly lower than those of the control group (aortic scores: 0.26 ± 0.20 vs. 0.60 ± 0.31, P < 0.05). In conclusion, the present study demonstrated, for the first time, that low-dose ketanserin prevented the development of atherosclerosis independent of its blood pressure lowering action in SHRs and New Zealand White rabbits at least in part via enhancement of arterial baroreflex function.
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Antihipertensivos/uso terapéutico , Aterosclerosis/prevención & control , Ketanserina/uso terapéutico , Antagonistas de la Serotonina/uso terapéutico , Animales , Aterosclerosis/fisiopatología , Barorreflejo/efectos de los fármacos , Presión Sanguínea/efectos de los fármacos , Femenino , Masculino , Conejos , Ratas , Ratas Endogámicas SHRRESUMEN
OBJECTIVES: This study was designed to evaluate the interaction between aging and obesity on cardiac contractile and intracellular Ca2+ properties. METHODS: Cardiomyocytes from young (4-mo) and aging (12- and 18-mo) male lean and the leptin deficient ob/ob obese mice were treated with leptin (0.5, 1.0 and 50 nM) for 4 hrs in vitro. High fat diet (45% calorie from fat) and the leptin receptor mutant db/db obesity models at young and older age were used for comparison. Cardiomyocyte contractile and intracellular Ca2+ properties were evaluated including peak shortening (PS), maximal velocity of shortening/relengthening (+/- dL/dt), time-to-PS (TPS), time-to-90% relengthening (TR(90)), intracellular Ca2+ levels and decay. O2(-) levels were measured by dihydroethidium fluorescence. RESULTS: Our results revealed reduced survival in ob/ob mice. Aging and obesity reduced PS, +/- dL/dt, intracellular Ca2+ rise, prolonged TR(90) and intracellular Ca2+ decay, enhanced O2(-) production and p(47phox) expression without an additive effect of the two, with the exception of intracellular Ca2+ rise. Western blot analysis exhibited reduced Ob-R expression and STAT-3 phosphorylation in both young and aging ob/ob mice, which was restored by leptin. Aging and obesity reduced phosphorylation of Akt, eNOS and p38 while promoting pJNK and pIkappaB. Low levels of leptin reconciled contractile, intracellular Ca2+ and cell signaling defects as well as O2(-) production and p(47phox) upregulation in young but not aging ob/ob mice. High level of leptin (50 nM) compromised contractile and intracellular Ca2+ response as well as O2(-) production and stress signaling in all groups. High fat diet-induced and db/db obesity displayed somewhat comparable aging-induced mechanical but not leptin response. CONCLUSIONS: Taken together, our data suggest that aging and obesity compromise cardiac contractile function possibly via phosphorylation of Akt, eNOS and stress signaling-associated O2(-) release.
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Envejecimiento/fisiología , Leptina/fisiología , Miocitos Cardíacos/fisiología , Obesidad/fisiopatología , Transducción de Señal/fisiología , Estrés Fisiológico , Animales , Señalización del Calcio/fisiología , Células Cultivadas , Grasas de la Dieta/administración & dosificación , Grasas de la Dieta/farmacología , Leptina/deficiencia , Masculino , Ratones , Ratones Obesos , Contracción Miocárdica , Miocitos Cardíacos/citología , Óxido Nítrico Sintasa de Tipo III/metabolismo , Proteínas Proto-Oncogénicas c-akt/metabolismo , Superóxidos/metabolismoRESUMEN
OBJECTIVE: Vagus nerve stimulation inhibits proinflammatory cytokine production by signaling through the alpha7 nicotinic acetylcholine receptor (alpha7nAChR). Anisodamine, a muscarinic acetylcholine receptor antagonist, has been used clinically in China for treatment of various shocks, but the mechanism was poorly understood. Here, we tested the hypothesis whether anisodamine attained its antishock effect through activation of alpha7nAChR. DESIGN: : Randomized and controlled in vitro and in vivo study. SETTINGS: Research laboratory and animal facility rooms. SUBJECTS: Sprague-Dawley rats, Kunming mice, alpha7nAChR-deficient mice, and RAW264.7 cells. INTERVENTIONS: Sprague-Dawley rats were injected with lipopolysaccharide (LPS) (15 mg/kg, intravenous) to induce septic shock. Methyllycaconitine, a selective alpha7nAChR antagonist, was administered (10 mg/kg, intraperitoneal) 10 minutes before anisodamine (10 mg/kg, intravenous). Mean arterial pressure was monitored and cytokines were analyzed 2 hours after the onset of LPS. In vagotomized mice and alpha7nAChR-deficient mice, the antishock effect of anisodamine was appraised, respectively. RAW264.7 cells were stained by fluorescein isothiocyanate- labeled-alpha-bungarotoxin and the fluorescence intensity was observed. Mice peritoneal macrophages were pretreated and stimulated with LPS, and tumor necrosis factor (TNF)-alpha in the supernatant was measured by enzyme-linked immunosorbent assay. MEASUREMENTS AND MAIN RESULTS: Methyllycaconitine significantly antagonized the beneficial effect of anisodamine on mean arterial pressure and TNF-alpha, interleukin-1beta expression in response to LPS. The antishock effects of anisodamine were markedly attenuated in vagotomized mice and alpha7nAChR-deficient mice. In vitro, anisodamine significantly augmented the effect of acetylcholine on fluorescence intensity stained with fluorescein isothiocyanate-labeled-alpha-bungarotoxin and TNF-alpha production stimulated with LPS. CONCLUSION: These findings demonstrate that the antishock effect of anisodamine is intimately linked to alpha7nAChR-dependent anti-inflammatory pathway.
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Agonistas Nicotínicos/farmacología , Receptores Nicotínicos/efectos de los fármacos , Choque Séptico/tratamiento farmacológico , Alcaloides Solanáceos/farmacología , Aconitina/análogos & derivados , Aconitina/farmacología , Animales , Secuencia de Bases , Línea Celular , China , Cartilla de ADN , Interleucina-1beta/metabolismo , Macrófagos Peritoneales/efectos de los fármacos , Macrófagos Peritoneales/metabolismo , Ratones , Agonistas Nicotínicos/uso terapéutico , Antagonistas Nicotínicos/farmacología , Reacción en Cadena de la Polimerasa , Ratas , Ratas Sprague-Dawley , Choque Séptico/metabolismo , Choque Séptico/fisiopatología , Alcaloides Solanáceos/uso terapéutico , Factor de Necrosis Tumoral alfa/biosíntesis , Factor de Necrosis Tumoral alfa/metabolismo , Vagotomía , Receptor Nicotínico de Acetilcolina alfa 7RESUMEN
Patients with Parkinson's disease (PD) often have attenuated baroreflex function, which may occur before the onset of PD-associated movement disorders. The aim of the present study was to test whether impaired arterial baroreflex (ABR) function could contribute to the pathogenesis of PD. 6-Hydroxydopamine (8 mug in 4 mul) was microinjected into the left substantia nigra of rats to establish unilateral PD models, and bilateral PD models were established in rats by administration of rotenone by osmotic minipump for four weeks, at a dose of 2.5 mg . kg(-1) . day(-1). An ABR dysfunction model was obtained by performing sinoaortic denervation (SAD). Hemodynamic variables were determined in conscious rats. PD-like symptoms and dopamine content in corpus striatum (CS) were also assessed. 6-Hydroxydopamine and rotenone treatment and SAD were associated with enhanced blood pressure variability (BPV) and blunted baroreflex sensitivity (BRS). Rotenone, but not SAD, significantly reduced dopamine content in the CS, induced catalepsy, and inhibited rearing and exploratory behavior. SAD before the administration of rotenone did not aggravate the rotenone-induced dopaminergic lesion. Our findings do not support the presumption that ABR dysfunction contributes to the pathogenesis of PD in rats.
Asunto(s)
Barorreflejo/fisiología , Enfermedad de Parkinson Secundaria/fisiopatología , Nodo Sinoatrial/fisiología , Animales , Conducta Animal/fisiología , Presión Sanguínea/efectos de los fármacos , Catalepsia/inducido químicamente , Catalepsia/psicología , Cuerpo Estriado/efectos de los fármacos , Cuerpo Estriado/metabolismo , Desnervación , Dopamina/metabolismo , Dopamina/fisiología , Frecuencia Cardíaca/efectos de los fármacos , Frecuencia Cardíaca/fisiología , Masculino , Oxidopamina , Enfermedad de Parkinson Secundaria/inducido químicamente , Ratas , Ratas Sprague-Dawley , RotenonaRESUMEN
1. The PC12 cell line, which was cloned from a rat adrenal phaeochromocytoma, is a useful model system. It expresses neuronal properties after treatment with nerve growth factor (NGF). The nervous system-specific P2X receptor subtype P2X(2) was initially cloned from PC12 cells, but little is known about the expression of other subtypes of P2X receptors in PC12 cells. The aim of the present study was to investigate whether PC12 cells express the other P2X receptors when exposed to NGF. 2. Reverse transcription-polymerase chain reaction at the mRNA level and immunocytochemisty at the protein level showed that, among the seven P2X purinoceptor subtypes, only P2X(2) was found to be expressed in undifferentiated PC12 phaeochromocytoma cells, but all seven P2X purinoceptor subtypes were expressed in differentiated PC12 cells treated with 50 microg/mL NGF. 3. Electrophysiological recordings indicated that ATP (30 micromol/L) but not alpha,beta-methylene ATP (alpha,beta-meATP; 30 micromol/L) evoked an inward current in undifferentiated PC12 cells, but both alpha,beta-meATP and ATP evoked inward currents in differentiated PC12 cells. The results indicate that the NGF-induced P2X receptors expressed in PC12 cells are functional channels. 4. The present study suggests that the NGF-induced neuronal phenotype of PC12 cells may be a model for the study of P2X heteromeric receptors.
Asunto(s)
Factor de Crecimiento Nervioso/farmacología , Receptores Purinérgicos P2/fisiología , Animales , Células PC12 , Técnicas de Placa-Clamp , ARN Mensajero/metabolismo , Ratas , Receptores Purinérgicos P2XRESUMEN
AIM: To test the effects of atenolol and amlodipine, either alone or in combination, on blood pressure, blood pressure variability (BPV), baroreflex sensitivity (BRS), and the prevalence of stroke in stroke-prone spontaneously hypertensive rats (SHR-SP). METHODS: In the first set of the study, 24 8-month-old, female SHR-SP rats were randomly divided into 3 groups. Blood pressure, heart period, and BRS were determined before and after the intragastric administration of atenolol (10 mg/kg) and amlodipine (1.0 mg/kg), either alone or in combination. In the second set of the study, 40 male and 40 female rats were randomly assigned to 1 of the following 4 groups: control, atenolol (10 mg.kg(-1).d(-1)), amlodipine (1.0 mg.kg(-1).d(-1)), and both (10 male and 10 female in each group). The stroke incident and survival time were recorded. RESULTS: Atenolol and amlodipine, either alone or in combination, significantly decreased blood pressure, with the exception of the amlodipine-induced effect on diastolic blood pressure. Meanwhile, only the combination treatment significantly decreased the BPV levels for the same period. The q-values calculated by the probability sum analysis were 1.17 and 2.67 for systolic and diastolic blood pressure, respectively, and were 2.48 and 2.10 for systolic and diastolic BPV, respectively, following administration. Neither drug exhibited any significant effect on BRS. Atenolol and amlodipine, either alone or in combination, significantly increased the lifespan of SHR-SP, with the best effect elicited by the combination therapy. CONCLUSION: A significant synergism exists between atenolol and amlodipine in lowering and stabilizing blood pressure in SHR-SP. Combination therapy may be an optimal strategy for the prevention of stroke in hypertension.
Asunto(s)
Amlodipino/administración & dosificación , Antihipertensivos/administración & dosificación , Atenolol/administración & dosificación , Presión Sanguínea/efectos de los fármacos , Accidente Cerebrovascular/prevención & control , Animales , Sinergismo Farmacológico , Quimioterapia Combinada , Femenino , Masculino , Ratas , Ratas Endogámicas SHR , Accidente Cerebrovascular/tratamiento farmacológico , Tasa de SupervivenciaRESUMEN
The present work was designed to establish a novel animal model for motion sickness (MS) in rodents and to evaluate the effects of a combination of scopolamine and modafinil on MS with this novel method. It was found that the rats and mice presented several symptoms induced by rotation such as, piloerection, tremble, urinal and fecal incontinence. As the rats and mice are lack of emesis response to rotation, we used a score based on abovementioned symptoms as an index for the severity of MS in rodents. MS index was determined in 260 mice with this novel method. It was found that the distribution of MS index was normal (W=0.99; P=0.23. P>0.05 considered values' normal distribution). The effects of scopolamine on MS were studied in mice and rats. It was found that scopolamine significantly decreased MS index at the dose of 0.3 mg/kg in mice and 1.0 mg/kg in rats. Finally, the effects of a combination of scopolamine and modafinil were observed with this novel method in rats. It was found that the efficacy of the combination (5.0+5.0 mg/kg) was greater than the single drugs (10 mg/kg). Even the smallest dose of the combination (0.5+0.5 mg/kg) had a similar effect to large dose of scopolamine or modafinile when they were used alone. In conclusion, this animal model is suitable for MS study in rats and mice and the combination of scopolamine and modafinil might be a new method to treat or prevent MS.